BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system
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Mattsson, Niklas, Rajendran, Lawrence, Zetterberg, Henrik, Gustavsson, Mikael, Andreasson, Ulf, Olsson, Maria, Brinkmalm, Gunnar, Lundkvist, Johan, Jacobson, Laura, Perrot, Ludovic, Neumann, Ulf, Borghys, Herman, Mercken, Marc, Dhuyvetter, Deborah, Jeppsson, Fredrik, Blennow, Kaj and Portelius, Erik (2012) BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system. PLosOne, 7 (2). e31084-e31084. ISSN 1932-6203
Abstract
BACE1 is a key enzyme for amyloid-β (Aβ) production, and an attractive therapeutic target in Alzheimer’s disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal Aβ metabolism, inducing a unique pattern of secreted Aβ peptides. Aβ peptides were analyzed in cell media from APP transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in Aβ1-40 and Aβ1-42, treatment also changed the relative levels of several other Aβ isoforms. In particular Aβ1-34 decreased, while Aβ5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in Aβ1-40 and Aβ1-42. The effects on Aβ5-40 indicate the presence of a BACE1 independent pathway of Aβ degradation. The described CSF Aβ pattern may be used as a pharmacodynamic fingerprint to detect biochemical effects of BACE1-therapies in clinical trials, which might accelerate development of novel therapies.
| Item Type: | Article |
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| Keywords: | β-amyloid, Alzheimer’s disease, BACE1, pharmacodynamic markers, mass spectrometry, β-secretase |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/6685 |